CN110183371A - A kind of preparation process of zafirlukast intermediate - Google Patents
A kind of preparation process of zafirlukast intermediate Download PDFInfo
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- CN110183371A CN110183371A CN201910288764.8A CN201910288764A CN110183371A CN 110183371 A CN110183371 A CN 110183371A CN 201910288764 A CN201910288764 A CN 201910288764A CN 110183371 A CN110183371 A CN 110183371A
- Authority
- CN
- China
- Prior art keywords
- methyl
- nitro
- indol
- zafirlukast
- tosyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960004764 zafirlukast Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 25
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052901 montmorillonite Inorganic materials 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 17
- -1 (5- nitro -1- tosyl -1H- indol-3-yl) methyl Chemical group 0.000 claims abstract description 13
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000006837 decompression Effects 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 230000008034 disappearance Effects 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 1
- 230000020477 pH reduction Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 abstract description 2
- 229940127554 medical product Drugs 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 6
- WJQWYAJTPPYORB-UHFFFAOYSA-N 5-nitro-2,3-dihydro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NCCC2=C1 WJQWYAJTPPYORB-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 229910001923 silver oxide Inorganic materials 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical class [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 1
- ZMLVUZAEKBEOER-UHFFFAOYSA-N 5-nitro-2,3-dihydro-1h-indole-3-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=C2NCC(C=O)C2=C1 ZMLVUZAEKBEOER-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
A kind of preparation process of zafirlukast intermediate, the compound are the important intermediates for preparing leukotriene antagonist drug zafirlukast.Using (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate and 3- methoxyl methyl benzoate as raw material; under the action of acid montmorillonite; in atent solvent; heating reaction to raw material disappears, and 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate is obtained by filtration；Under alkaline condition, hydrolysis obtains target product to above compound.The present invention provides a kind of new technology route of synthesis zafirlukast important intermediate, have easy to operate, reaction cost is low, and product yield is high, and environmental-friendly technological merit can meet medical product large-scale production demand.
Description
Technical field
The invention belongs to the production fields of fine chemical product, in particular to a kind of to treat among asthmatic medicament zafirlukast
The preparation process of body.
Background technique
With the continuous development of process of industrialization, the living environment of the mankind also occurs constantly to change, under air quality
Drop, along with hundreds of millions of smoking populations, the quantity of China big city asthmatic patient increases year by year.Zafirlukast
(Zafirlukast), entitled [3- [2- methoxyl group -4- [(2- tolyl) sulfoamido carbonyl] benzyl] -1- methyl-1 H- of chemistry
Indoles -5- methylene] carbamic acid ring pentyl ester, it is a kind of leukotriene receptor antagonists of Astrazeneca AB, Britain exploitation, faces
Bed is used for the prevention and long-term treatment of asthma.Currently, the market price of zafirlukast is more expensive, preparation process is also relatively
Complexity, the synthesis technology for being mainly reflected in the intermediate of zafirlukast have too low yield, post-processing complexity, generation more
The biggish defect of " three wastes " environmental pollution, is unfavorable for the needs of large-scale industrial production.Therefore, develop zafirlukast and its
The preparation process of important intermediate will bring preferable economic benefit and social benefit.
The structure of zafirlukast is as follows:
3- methoxyl group -4- [(1- methyl -5- amino -1H- indol-3-yl) methyl] benzene in the molecular structure of zafirlukast
Formic acid is the nuclear structure unit of the compound.The precursor compound of the structural unit is 3- methoxyl group -4- [(5- nitro -1H-
Indol-3-yl) methyl] benzoic acid, i.e. formula (I) compound, structure be as follows.Therefore, which is prepared into bundle
The key problem in technology of Lu Site preparation process.
Currently, the synthesis zafirlukast intermediate of existing literature report mainly has three routes.Route one: with 5- nitro Yin
Diindyl is raw material, and 4- bromomethyl -3- methoxyl methyl benzoate is alkylating reagent, under silver oxide effect, passes through friedel-craft alkyl
Change to react and obtains 3- methoxyl group -4- (5- nitroindoline -3- methylene) methyl benzoate, total recovery about 45% (Li Wei, Ning Qi,
Synthesis [J] Chinese Journal of Pharmaceuticals of zafirlukast, 2004,35 (8): 451-452；Brown FJ,Bemstein PR,
Yee YK,et al,Heter℃ yclic amide derivatives,US,4859692).In the reaction, expensive
Silver oxide and toxicity halogenated aryl hydrocarbon use, strongly limit application of this method in large-scale production.Route two:
Under lewis acid effect, using 5- nitroindoline as raw material, 3- methoxyl group -4- methoxycarbonyl group chlorobenzoyl chloride is acylting agent, is led to
It crosses friedel-craft acylation and carbonyl reduction two-step reaction obtains 3- methoxyl group -4- (5- nitroindoline -3- methylene) benzoic acid first
Ester, total recovery about 70% (Yang Limin, a kind of preparation method of new zafirlukast important intermediate, CN101104601A).It should
The condition to high temperature (180~200 DEG C) and highly basic, although reaction yield is higher, the reaction of high temperature, highly basic are used in reaction
Requirement of the condition to equipment is high, and product quality is difficult to ensure.Route three: with 5- nitroindoline and 3- methoxyl group -4- formoxyl
Methyl benzoate is raw material, under the catalysis of boron trifluoride/ether, prepares 3- methoxyl group -4- by reduction-alkylated reaction
(5- nitroindoline -3- methylene) methyl benzoate, yield 52% (Mahadevan A, Sard H, Gonzalez M, McKew
JC,A general method for C3reductive alkylation of indoles,Tetrahedron
Letters,2003,44:4589-4591).The reaction is easy to produce bisindole by-product, leads to the purification ratio of target product
It is more difficult.Above-mentioned zafirlukast intermediate 3- methoxyl group -4- (5- nitroindoline -3- methylene) methyl benzoate can be further
Hydrolysis obtains formula (I) compound.
In conclusion these methods all have one although there is many technological means to prepare zafirlukast intermediate at present
Fixed disadvantage: raw material/reagent is prohibitively expensive, and lewis acid causes impurity to increase as catalyst, purification difficult etc..Therefore, exist
A kind of efficient there is still a need for developing in this field, easy to operate, product purity is high, the high-quality bundle suitable for large-scale production
The preparation process of Lu Site intermediate.
Summary of the invention
The technical issues of solution: the invention aims to solve the deficiency of above-mentioned background technique, a kind of zafirlukast is provided
The preparation process of intermediate, has easy to operate, and reaction cost is low, and product yield is high, and environmental-friendly technological merit can meet
Medical product large-scale production demand.
Technical solution: a kind of preparation process of zafirlukast intermediate, shown in structure such as formula (I),
Step are as follows:
A. (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate and 3- methoxy are added into atent solvent
Yl benzoic acid methyl esters, adds acid montmorillonite, is heated to 30-45 DEG C of reaction 1-6h and filters off after TLC measures raw material disappearance
Except acid montmorillonite, 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] benzoic acid first is obtained
Ester；By quality ratio it is (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate: 3- methoxyl methyl benzoate:
Acid montmorillonite=2.3:1:2；
B. 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate is dissolved in
In methanol, 2M potassium hydroxide aqueous solution is added, is heated to 60 DEG C of reaction 4h and adjusts pH to 7 after TLC measures raw material disappearance, be precipitated
Faint yellow solid, decompression filter and obtain target product formula (I) compound；Dosage is with molar ratio computing, 3- methoxyl group -4- [(5- nitro
- 1- tosyl -1H- indol-3-yl) methyl] methyl benzoate: potassium hydroxide=1:(2~10).
Preferably, atent solvent described in step a is methylene chloride, chloroform or 1,2- dichloroethanes.
Preferably, acid montmorillonite described in step a be trifluoroacetic acid acid montmorillonite, trichloroacetic acid acid montmorillonite or
Concentrated hydrochloric acid acid montmorillonite.
The synthetic route of zafirlukast important intermediate formula (I) compound is as follows in the present invention:
By the above-mentioned description of this invention it is found that the present invention provides a kind of new works for synthesizing zafirlukast important intermediate
Skill route, it is entirely different with the synthetic route of the zafirlukast intermediate of existing literature report, it is the new breakthrough of this field.This hair
Synthesis material (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate of bright use is referred to report document
(Che Z, Zhang S, Shao Y., et al, J.Agric.Food Chem.2013,61,5696-5705) large scale preparation,
Required chemical reagent is cheap and easy to get.The synthesis material 3- methoxyl methyl benzoate that the present invention uses belongs to conventional reagent, can
Directly to buy.The acid montmorillonite that the present invention uses is to handle extensive system through Bronsted acid by cheap common montmorillonite
Standby, there is safety and environmental protection, reusable advantage.
The utility model has the advantages that being avoided toxic due to using a kind of new technology route for synthesizing zafirlukast important intermediate
Halide reagent and acyl chlorides reagent use；Meanwhile using acid montmorillonite substitution pollution big lewis acid and valuableness
Silver oxide only needs filtering that can remove after reaction；In addition, preparation process provided by the invention needs two-step reaction, pass through weight
Method for crystallising obtains high purity product, and total recovery reaches 73%, is better than reported synthetic method.In short, the present invention provides
A kind of new technology route synthesizing zafirlukast important intermediate, has easy to operate, and post-processing is easy, and production cost is low, produces
The advantages of product high income, purity is high, safety and environmental protection, is relatively suitble to large-scale industrial production.
Specific embodiment
The present invention will be illustrated by following specific embodiments, but not limited by this embodiment.
Embodiment 1
The preparation of (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate:
In 250mL round-bottomed flask, 5- nitroindoline -3- formaldehyde (19g, 0.1mol) is added and is dissolved in dry two of 150mL
In chloromethanes, paratoluensulfonyl chloride (19.1g, 0.1mol) and potassium carbonate (27.6g, 0.2mol) are sequentially added, is heated to reflux
Reaction 12 hours.TLC measures raw material and disappears, and is cooled to room temperature, and stands, and filters, and filtrate decompression distillation removal organic solvent obtains
Yellow solid 29g.In 250mL round-bottomed flask, above-mentioned 29g yellow solid is dissolved in 100mL ethyl alcohol, is added in batches under stirring
Enter sodium borohydride (6.4g, 0.17mol), reacts at room temperature 6 hours.TLC measures raw material and disappears, and 1M aqueous hydrochloric acid solution adjusts pH to 7,
Ethyl acetate extracts (3 × 50mL), merges organic layer, organic layer saturated common salt water washing, anhydrous sodium sulfate drying.Decompression is steamed
Dry solvent obtains light yellow oil 28g.In 250mL round-bottomed flask, above-mentioned 28g light yellow oil is dissolved in 60mL
It in acetic anhydride, is added with stirring 4-dimethylaminopyridine (1.0g, 0.08mol), reacts at room temperature 2 hours.TLC measurement raw material disappears
It loses, most of organic solvent is removed under reduced pressure, elutriation is added to go out faint yellow solid, decompression filters, and recrystallizes through ethyl acetate/hexamethylene
Obtain white solid (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate (28g, 3 step gross production rates 72%).1H
NMR (400MHz, DMSO-d6) δ 8.56 (d, J=2.1Hz, 1H), 8.20 (dd, J=9.2,2.2Hz, 1H), 8.16-8.11
(m, 2H), 7.92 (d, J=8.4Hz, 2H), 7.40 (d, J=8.3Hz, 2H), 5.25 (s, 2H), 2.29 (s, 3H), 2.00 (s,
3H)；13C NMR(101MHz,DMSO-d6)δ170.9,147.0,144.3,137.7, 134.1,131.1,129.9,129.7,
127.5,120.7,118.9,117.2,114.5,57.3,21.6,21.2；ESI MS m/z 389.4 [M+H]+.
The preparation of acid montmorillonite:
In 2L round-bottomed flask, montmorillonite (200g) and 3% aqueous hydrochloric acid solution (1.2L) is added, is heated to 100 DEG C, stirring
24 hours.Filtering, filter cake are washed with distilled water (1.5L), are placed in baking oven and activate 6 hours at 100 DEG C, be put into drier
It is spare.
The preparation of 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate:
In 250mL round-bottomed flask, (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate is added
(19.4g, 0.05mol) and 3- methoxyl methyl benzoate (8.4g, 0.05mol) are dissolved in 100mL methylene chloride, under stirring
It is added acid montmorillonite (16.8g), is heated to 45 DEG C of back flow reactions 4 hours.TLC measures raw material and disappears, and is cooled to room temperature, quiet
It sets, filters, filtrate decompression distillation removal organic solvent obtains yellow solid, is recrystallized to give white through ethyl acetate/hexamethylene
Solid 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate (18.4g, yield
74%).1H NMR (400MHz, DMSO-d6) δ 8.42 (d, J=2.0Hz, 1H), 8.17 (dd, J=9.1,2.1Hz, 1H),
8.03 (d, J=9.1Hz, 1H), 7.72 (d, J=8.3Hz, 2H), 7.59-7.51 (m, 2H), 7.41 (s, 1H), 7.24 (d, J
=8.3Hz, 2H), 7.13-7.05 (m, 1H), 4.04 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 2.36 (s, 3H)；13C
NMR(101MHz, DMSO-d6)δ166.9,157.0,145.9,144.1,138.2,134.7,132.2,130.8,130.2,
129.8,126.9,126.7, 122.3,120.0,116.5,113.9,111.3,55.7,52.3,25.4,21.8；ESI MS
m/z 495.4[M+H]+.
The preparation of 3- methoxyl group -4- [(5- nitro -1H- indol-3-yl) methyl] benzoic acid:
In 250mL round-bottomed flask, it is added 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl)
Methyl] methyl benzoate (15.0g, 0.03mol) is dissolved in 80mL methanol, it is added with stirring 2M potassium hydroxide aqueous solution
(40mL) is heated to 60 DEG C and reacts 4 hours.TLC measures raw material and disappears, and 1M aqueous hydrochloric acid solution adjusts pH to 7, and pale yellow colored solid is precipitated
Body, decompression filter, and are recrystallized to give white solid 3- methoxyl group -4- [(5- nitro -1H- indoles -3- through ethyl acetate/hexamethylene
Base) methyl] benzoic acid (9.7g, yield 98%).1H NMR (400MHz, DMSO-d6) δ 11.60 (s, 1H), 8.44 (d, J=
2.0 Hz, 1H), 7.92 (dd, J=8.9,2.2Hz, 1H), 7.48-7.37 (m, 5H), 7.19 (d, J=7.8Hz, 1H), 4.07
(s,2H), 3.88(s,3H)；13C NMR(101MHz,DMSO-d6)δ167.7,157.1,140.8,139.9,134.8,
130.6,130.2, 127.9,126.8,122.3,116.9,116.3,116.2,112.4,111.4,56.0,25.1；ESI MS
m/z 349.4[M+Na]+.
Embodiment 2
The preparation of 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate:
In 250mL round-bottomed flask, (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate is added
(9.7g, 0.025mol) and 3- methoxyl methyl benzoate (4.2g, 0.025mol) are dissolved in 50mL chloroform, under stirring
It is added acid montmorillonite (8.4g), is heated to 45 DEG C of back flow reactions 4 hours.TLC measures raw material and disappears, and is cooled to room temperature, and stands,
It filters, filtrate decompression distillation removal organic solvent obtains yellow solid, is recrystallized to give white solid through ethyl acetate/hexamethylene
3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate (8.1g, yield
66%).
Embodiment 3
The preparation of 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate:
In 250mL round-bottomed flask, (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate is added
(9.7g, 0.025mol) and 3- methoxyl methyl benzoate (4.2g, 0.025mol) are dissolved in 50mL1, in 2- dichloroethanes, stir
Lower addition acid montmorillonite (8.4g) is mixed, is heated to 45 DEG C of back flow reactions 4 hours.TLC measures raw material and disappears, and is cooled to room temperature,
It stands, filters, filtrate decompression distillation removal organic solvent obtains yellow solid, is recrystallized to give through ethyl acetate/hexamethylene white
Color solid 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate (7.8g, yield
63%).
Claims (3)
1. a kind of preparation process of zafirlukast intermediate, shown in structure such as formula (I),
It is characterized in that, step are as follows:
A. (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate and 3- methoxybenzene are added into atent solvent
Methyl formate adds acid montmorillonite, is heated to 30-45 DEG C of reaction 1-6h and filters off deacidification after TLC measures raw material disappearance
Change montmorillonite, obtains 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate；With
Mass ratio is calculated as (5- nitro -1- tosyl -1H- indol-3-yl) methyl acetate: 3- methoxyl methyl benzoate: acidification
Montmorillonite=2.3:1:2；
B. 3- methoxyl group -4- [(5- nitro -1- tosyl -1H- indol-3-yl) methyl] methyl benzoate is dissolved in methanol
In, 2 M potassium hydroxide aqueous solutions are added, is heated to 60 DEG C of reaction 4h and adjusts pH to 7 after TLC measures raw material disappearance, be precipitated light
Yellow solid, decompression filter and obtain target product formula (I) compound；Dosage is with molar ratio computing, 3- methoxyl group -4- [(5- nitro -
1- tosyl -1H- indol-3-yl) methyl] methyl benzoate: potassium hydroxide=1:(2~10).
2. the preparation process of zafirlukast intermediate according to claim 1, it is characterised in that: inertia described in step a
Solvent is methylene chloride, chloroform or 1,2- dichloroethanes.
3. the preparation process of zafirlukast intermediate according to claim 1, it is characterised in that: be acidified described in step a
Montmorillonite is trifluoroacetic acid acid montmorillonite, trichloroacetic acid acid montmorillonite or concentrated hydrochloric acid acid montmorillonite.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86103278A (en) * | 1985-04-17 | 1986-12-17 | 帝国化学工业泛美公司 | The method for preparing heterocyclic amide derivative |
| CN101104601A (en) * | 2006-07-14 | 2008-01-16 | 海南盛科生命科学研究院 | Method for preparing zafirlukast important intermediate |
| US20090012146A1 (en) * | 2007-07-02 | 2009-01-08 | Giridhar Reddy Buggana | Solubility-enhanced pharmaceutical compositions comprising zafirlukast |
| CN101585799A (en) * | 2009-06-19 | 2009-11-25 | 中国科学院上海有机化学研究所 | Method for preparing unsymmetrical bis(indolyl)methane compound |
| WO2013010881A1 (en) * | 2011-07-18 | 2013-01-24 | Almirall, S.A. | NEW CRTh2 ANTAGONISTS |
| CN104910061A (en) * | 2015-06-03 | 2015-09-16 | 渤海大学 | Preparation technology of zafirlukast intermediate |
| CN105367478A (en) * | 2015-06-03 | 2016-03-02 | 北京成宇药业有限公司 | Preparation process of zafirlukast |
| CN108084077A (en) * | 2017-12-20 | 2018-05-29 | 江汉大学 | A kind of synthetic method of zafirlukast intermediate |
-
2019
- 2019-04-11 CN CN201910288764.8A patent/CN110183371B/en not_active Expired - Fee Related
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86103278A (en) * | 1985-04-17 | 1986-12-17 | 帝国化学工业泛美公司 | The method for preparing heterocyclic amide derivative |
| CN101104601A (en) * | 2006-07-14 | 2008-01-16 | 海南盛科生命科学研究院 | Method for preparing zafirlukast important intermediate |
| US20090012146A1 (en) * | 2007-07-02 | 2009-01-08 | Giridhar Reddy Buggana | Solubility-enhanced pharmaceutical compositions comprising zafirlukast |
| CN101585799A (en) * | 2009-06-19 | 2009-11-25 | 中国科学院上海有机化学研究所 | Method for preparing unsymmetrical bis(indolyl)methane compound |
| WO2013010881A1 (en) * | 2011-07-18 | 2013-01-24 | Almirall, S.A. | NEW CRTh2 ANTAGONISTS |
| CN104910061A (en) * | 2015-06-03 | 2015-09-16 | 渤海大学 | Preparation technology of zafirlukast intermediate |
| CN105367478A (en) * | 2015-06-03 | 2016-03-02 | 北京成宇药业有限公司 | Preparation process of zafirlukast |
| CN108084077A (en) * | 2017-12-20 | 2018-05-29 | 江汉大学 | A kind of synthetic method of zafirlukast intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 陈明鲁等: ""扎鲁司特合成路线图解"", 《中国医药工业杂志》 * |
| 陈明鲁等: ""扎鲁司特合成路线图解"", 《中国医药工业杂志》, vol. 42, no. 5, 31 December 2011 (2011-12-31), pages 393 - 395 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111675644A (en) * | 2020-06-08 | 2020-09-18 | 南京医科大学 | Indole diaryl methane compound and preparation method and application thereof |
| CN111675644B (en) * | 2020-06-08 | 2022-12-23 | 南京医科大学 | Indole diaryl methane compound and preparation method and application thereof |
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